Sarcosine NCA

Waley and Watson (14) were the first to report a kinetic study of this process. They initiated the polymerisation of sarcosine NCA by a... 

The pioneering work of Waley and Watson (14) was soon extended and elaborated by the studies of Ballard and Bamford (20). They showed that some of the complex features of the kinetics of sarcosine NCA polymerisation, which were reported by the former workers, arose from the catalytic action of carbon dioxide. As the reaction progressed, the pressure of COs increased in Waley and Watson s reactor, and hence the contribution of the C02 catalysis became time-dependent. To avoid the problem of variable COa pressure, Ballard and Bamford developed a technique in which the pressure of C02 was kept constant and the rate of polymerisation was then determined by measuring the increase in C02 s volume. 

The carbamic adds may catalyse the polymerisation, and indeed, in the polymerisation of sarcosine NCA the catalytic effect of weak carboxylic adds, such as a-picolinic, was demonstrated (20). The polymerisation becomes inhibited, however, at high acid concentration, or on addition of a strong add such as o-nitro-benzoic, since the decrease in the concentration of the base, caused by its conversion into salts, outweighs the catalytic effect of the acid. This, indeed, is seen in Fig. 5. 

Apparently, the rate of polymerisation of sarcosine NCA is not entirely determined by the rate of formation of the adduct. The enhancing... 

The detailed mechanism of sarcosine NCA polymerisation may be radically modified by a change of solvent. For example, in dimethyl formamide this reaction is first order with respect to growing ends [see e. g. ref. (44)] instead of being second order as in nitrobenzene. The higher acidity of the former solvent reduces the basicity of the dissolved amine and, therefore, destroys its catalytic action. This effect influences also the equilibrium between the amine and the dissolved C02. In nitrobenzene, the carbamic acid produced is associated with the free amine forming the respective ammonium salt (ion-pairs), whereas in the more acidic dimethyl formamide it exists as an un-ionised acid. 

In principle, the addition is reversible and, if the rupture of the C(5)—0(1) bond of NCA adduct is sufficiently slow, an equilibrium may be established between the adduct, the monomer and the initiating or propagating base. The polymerisation of sarcosine NCA seems to be an example. 

Fig. 7. Conversion-time curves for polymerization of NCA s (0.224 mole l l) with amines (0.015 mole l-1) at 25 C in iV.iV-dimethylformamide. O y-Ethyl-L-glutamate NCA-di-isopropylamme A y-Ethyl-L-glutamate NCA-n-hexyl-amine Q Sarcosine NCA-di-isopropylaraine Sarcosine NCA-n-hexylamine. (Reprinted from paper by C, H. Bamford, and H. Block Polyamino Acids, Polypeptides and Proteins, p, 65, Wisconsin University Press 1962 (Fig. 7)3...

Tertiary amines were amongst the first initiators of NCA polymerisation which had been described in the literature and it seems that the polymerisation of all the known NCA s may be accomplished by their action. Wessely (77) reported in 1925 that glycine and phenyl alanine NCA s are readily polymerised in pyridine at ambient temperatures, and in the following paper (72) he reported a similar polymerisation of sarcosine NCA. The polypeptides produced by this initiator apparently formed cyclic polymers since no terminal end groups could be detected 41). It is significant that appreciable quantities (a few %) ot 3-acetic-hydantoin derivatives were found in the polymers formed from glycine and phenyl alanine NCA s but none was detected in the polymerised sarcosine NCA (72). This evidence suggests that the mechanisms of polymerisation initiated by aprotic bases may be different for the non-N-substituted NCA and the N-substituded anhydrides. 

Ballard and Bamford (43) also investigated the kinetics of the polymerisation of D,L-phenyl alanine NCA initiated by tributyl amine in nitrobenzene. This reaction does not ensue1 in pure tertiary amine (11), but it proceeds rapidly in polar solvents. (For a tentative explanation of this observation see p. 49.) However, the polarity does not appear to be a necessary condition for a rapid reaction since a fast polymerisation initiated by triethyl amine in benzene was observed by Blout (49). It seems, therefore, that the role of solvent in these reactions needs further and extensive examination (see also p. 48). In the tributylamine-initiated polymerisation, sarcosine NCA again proved to be inert (44) under conditions which led to a rapid polymerisation of the non-N-substituted NCA s. 

As shown in Fig. 7, sarcosine NCA, the N-substituted anhydride, polymerises faster than y-ethyl-L-glutamate NCA if the polymerisation... 

It should be remarked, at this juncture, that Bamford s experiments utilising 3-methyl hydantoin as a co-catalyst do not shed light on the problem of propagation. They have shown, merely, that a proton is required for the simple amine-piropagated polymerisation and, according to his scheme, any proton donor may suffice to produce this result (see however the footnote on p. 44). For example, if his mechanism is correct, sarcosine NCA should not be polymerised by sodium methoxide in a rigorously aprotie medium1, but polymerisation should ensue on... 

As shown in Table 9 acetylation of polysarcosine destroys the effect and the addition of such a polymer to phenylalanine dimethyl amide only slightly accelerates the process. (5) No effect is observed when sarcosine NCA is block-polymerised in poly-D.L-phenylalanine. 

It has been established that the polymerization of sarcosine NCA can be initiated by tertiary bases [18] and chloride ion [37] when (XI) is... 

Fig. 1. Conversion—time curves for the polymerization of 7-ethyI-L-glutamate NCA (0.2 mole 1 ) in Af,Al-dimethylformamide by pyridine and homologues (2.0 mole 1" ) at 25°C. o 2,6-lutidine, a-picoline, A pyridine. The broken curve shows a comparative experiment with sarcosine NCA (0.2 mole 1" ) and 2,6-lutidine (2.0 mole 1" ). Bamford and Block [ 19 ].

Fig. 2. Conversion—time curves for polymerization of NCAs (0.224 mole 1 ) initiated by amines at 25°C in i i,AT-dimethylformamide solution, o 7-ethyl-L-glutamate NCA/di-isopropylamine, sarcosine NCA/n-hexylamine, 7-ethyl-L-glutamate NCA/n-hexylamine, Dsareosine NCA/di-isopropylamine. Bamford and Block [22],...

The presence of a substituent in the 3-position of the NCA precludes equilibrium (6) and hence prevents the occurrence of reaction (18). It follows that, on the basis of the mechanisms described above, such NCA s should not polymerize unless a protic base (for example a primary or secondary amine) or other source of protons (for example, 3-methyl hydantoin) is present. If it could be established that polymerization does proceed with an aprotic base in aprotic media then some other mechanism of polymerization must be operative. This matter has been of central importance in discussions of various mechanisms of polymerization which have been advanced (Section 3). Experimentelly, it is not easy to obtain definitive evidence because of the high sensitivity of NCA s to protonic impurities (such as water and alcohols) in the presence of bases. It has been shown [18, 19, 38a] that proline NCA (X) and sarcosine NCA (I Ri = R2 = H, R3 = CH3) do not polymerize in the presence of tertiary bases under strictly aprotic conditions. With alkoxides, realization of such conditions is difficult, but it would appear that, at least with proline NCA, such strong bases can bring about ionization of the methine hydrogen and hence initiate polymerization as shown in (26). Evidence for this mechanism is provided by the observation that while sodium methoxide enriched... 

Fig. 4. Dependence of first-order rate coefficient for the polymerization of sarcosine NCA in AT,Al-dimethylformamide on concentration of preformed polymer [I]o in the absence and presence of hydrocinnamic acid. Zero CO2 pressure and 25°C. Hydrocinnamic acid concentrations Zero, o 2.5 x 10 mole 1" 2.5 x 10 ...

Fig. 7. Polymerization of sarcosine NCA in benzene at 25°C initiated by n-hexyl- ine. [NCAlo = 0.100 mole I, [n-hexylamineJo = 10 mole 1. Axis on right P = mean size of growing polymer chains. The arrow marks the point at which separation of polymer begins. Ballard and Bamford [70].

Scheme 197 Preparation of Sarcosine-NCA and use in the preparation of oligomers for lipopeptides.

Despite the drawbacks of this method, it has been used to prepare a tremendous number of polypeptide hybrid block copolymers (Table 1), and when carefully executed provides reasonably well-defined samples. Synthetic polymer domains have been prepared by addition polymerization of conventional vinyl monomers, such as styrene and butadiene, as well as by ringopening polymerization in the cases of ethylene oxide and e-caprolactone. The generality of this approach allows NCA polymerization off of virtually any primary amine functionality, which was exploited in the preparation of star block copolymers by polymerization of sarcosine NCA from an amine-terminated trimethyleneimine dendritic core [37]. In most examples, the polypeptide domain was based on derivatives of either lysine or glutamate, since these form a-helical polypeptides with good solubility characteristics. These residues are also desirable since, when deprotected, they give polypep-... 

Primary amine-catalyzed polymerization of NCAs in various solvents revealed that certain polar solvents themselves act as catalysts [3]. Characteristic for the catalytically active solvents is a relatively high nucleophihcity [4] (see left column in Table 15.1). This observation and the formation of cyclic polypeptides from the N-substituted sarcosine-NCA evidenced that a zwitterionic polymerization mechanism was catalyzed, which involves ROP and condensation steps (see Formula 15.2). Pyridine is known for many decades to activate carboxylic anhy-drdies by charge separation, i. e., formation of carboxylate anions plus N-acyl pyridinium ions Therefore, it is obvious that pyridine catalyzes the same zwitterionic mechanism as the nucleophilic polar solvents [5]. In the case of N-un-substitued NCAs the initiation step will be again a charge separation, but instead of... 

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